Veterans who suffered severe traumatic brain injury (TBI) are burdened by chronic neurological deficits and are at increased risk for developing chronic neurodegenerative disorders such as Alzheimer's disease (AD) later in life. Currently, there are no effective treatments for improving long-term functional recovery and reducing the risk of AD in TBI survivors. Thus, successful rehabilitation of brain-injured veterans and prevention of chronic disability is an area of medical research that warrants intensive investigation. Our preliminary data demonstrated that a single post-injury injection of memantine, an FDA approved drug for treatment of cognitive deficits in AD patients, improved neurological outcome acutely after experimental TBI in rats. However, the degree to which memantine therapy after TBI can improve long-term recovery, enhance neuronal repair and reduce secondary injury processes such as brain inflammation, brain hypoperfusion, and accumulation of amyloid-2 (A2) peptide (all of which contribute to the etiology of AD), remains to be determined. We propose a series of experiments that will directly address these issues by performing experimental controlled cortical impact (CCI) brain injury in rats and in a mouse model of AD. Aim 1: We will perform a dose response analysis of chronic (3 weeks) daily memantine administration on histopathology and neurological recovery in rats after CCI injury (Aim 1a). We will also determine if the beneficial effects of the 3-week treatment will be sustained over an extended chronic (3 month) recovery period, or if prolonged daily treatment is necessary to achieve long-term beneficial effects (Aim 1b). Aim 2: We will assess whether memantine can act as a cognitive enhancer after TBI by administering the drug only during the time of behavioral testing (days 14-19 post injury). We will also determine if potential cognitive enhancing effects are transient or sustained by re-testing the animals 3 months after injury. Aim 3: We will determine if chronic functional outcome after TBI can be improved further by combining memantine therapy with simvastatin therapy, an FDA approved lipid lowering drug. Aim 4: We will examine if memantine and/or combined memantine/simvastatin therapy can suppress post- injury increases in the neurotoxic amyloid-2 (A2) peptide, a molecule central to the pathogenesis of AD. We will achieve this by using a unique mouse model that has been modified genetically to produce human A2 (hA2), which differs from rodent A2 in that it is toxic to neurons and synapses. Aim 5: Analyses proposed in Aim 4 will be complemented by measurements of cerebral blood flow, which is impaired after TBI and influenced by A2 concentrations, and can contribute to the development of AD. In all experiments, we will assess motor, vestibular, and memory function at three weeks and/or three months after injury, as appropriate. Endpoint analyses will include histological analyses of lesion size, cell number, synapse density, microglia/astrocyte activation, A2 concentrations, as well as levels of recovery-promoting brain derived neurotrophic factor and soluble amyloid precursor protein alpha. Collectively, these experiments will determine if chronic memantine therapy is an effective way of improving rehabilitation after TBI, allowing for its quick translation into clinical practice for treatment of injured veterans. PUBLIC HEALTH RELEVANCE: Traumatic brain injury (TBI) is a major cause of disability in the veteran population and it places a considerable burden on the health care system. Additionally, TBI is a risk factor for developing Alzheimer's disease (AD), a devastating neurological disorder of particular relevance to the aging veteran population. This proposal examines the therapeutic potential of memantine, an FDA approved drug used to treat AD patients, to improve chronic recovery of neurological function after severe TBI and reduce post-injury pathological changes that confer risk of developing AD later in life. If therapeutic efficacy of memantine intervention in the rat and hA2 mouse model of brain injury proves successful, this therapy can be rapidly translated to the clinical setting to improve rehabilitation and quality of life of brain injured veterans.